The studies proposed here will investigate the molecular mechanism of sensory transduction in the vomeronasal organ (VNO). Convergent lines of evidence have shown that transduction cascades elicited by olfactory signals in the main olfactory epithelium (MOE) and by pheromone signals in the VNO are different. However, functional and molecular characteristics of the VNO signal transduction machinery are still largely unknown. In particular, both molecular and physiological approaches have failed, so far, to determine the nature and the mode of activation of the conductance that is activated by pheromone signals, and leads to generation of action potentials. We developed a cloning strategy based on differential screening of cDNA libraries constructed from individual VNO neurons, which led to the isolation of two independent families of genes likely to encode mammalian pheromone receptors. We intend to use a similar strategy in order to identify signal transduction components involved in pheromone mediated signaling. This cloning effort will not make any assumption about the nature of the genes encoding signal transduction components, but will rather take advantage of the different signaling mechanisms that are expressed in MOE and VNO neurons, and that distinguish subpopulations of VNO neurons. Direct analyses of the responses of VNO neurons to physiologically relevant stimuli have been very difficult as few pheromones have been characterized. We intend to use the powerful tools of mouse genetics to develop a transgenic mouse model in which to study the physiological response of VNO neurons to known ligands. This will allow the functional dissection of signal transduction pathways that translate pheromone signals into neural activity, leading to the generation of stereotyped behaviors and neuroendocrine changes.